Aromatic amino antispasmodic compounds



United States Patent 3,135,7 97 AROMATIC Alt 1N0 ANTISPASMODIC COMPOUNDSJohn H. Eiel, Milwaukee, Wis., assignor, by rnesne assignments, toColgate-Palmolive Company, a corporation of Delaware N0 Drawing. FiledApr. 15, 1958, Ser. No. 725,565

Claims. (Cl. 260570.6)

This invention relates to antispasmodic compounds which relieve thespasms of smooth muscles, particularly those of the gastro-intestinaltract, the lung, and the vascular system, and to new intermediates fromwhich they are produced.

This application is a continuation-in-part of my copending applicationsSerial No. 469,305, filed November 16, 1954, now abandoned, and SerialNo. 669,412, filed July 2, 1957, now abandoned; Serial No. 469,305 is acontinuation-in-part of my application Serial No. 230,249, filed June 6,1951, now abandoned.

A great deal of work has been done in developing antispasmodic compoundssuch as epinephrine to relieve the spasma of smooth muscles in thegastrointestinal tract and the bronchial tubes. In evaluating theusefulness of these antispasmodics, five interrelated factors need to beconsidered, (1) bronchodilator activity, (2) general anti spasmodicactivity, (3) period of eifectiveness, i.e., whether the action isfleeting or prolonged, (4) deleterious side effects, and (5) the modesin which the substance may be efiectively administered. The clinicalusefulness of these compounds is greatly limited in that they have aWeak and fleeting action, a high incidence of undesirable and sometimesdeleterious side etfects, and/or are limited by the mode in which theycan be administered.

1 have discovered and synthesized a group of new, superior antispasmodiccompounds of the formula on R no I CH-OHz-NH-YQ H0 Formula I phenylgroup is unsubstituted (R is hydrogen) and this is particularly so inhumans. In addition, those compounds in which Y is a tertiary branchedlower alkylene group are considered more useful than the'cornpounds inwhich Y is a straight chain (secondary) alkylene group or a branchedquaternary alkylene group. Also, the presence of a methyl group on thecarbon alpha to the nitrogen group often favors increased activity. Themost useful compounds of the series are those in which Y is a2-isopropyl group and R is a 3,4-methylenedioxy or a p-methoXy group onthe phenyl group.

3,135,797 Patented June 2, 1964 ice The production of these compounds isreadily effected by reacting chloroacetylcatechol with a nuclearsubstituted phenylalkylamine. to produce an intermediate3,4-dihydroxyphenyl N-(substituted phenylalkyl) -aminomethyl ketonewhich is then reduced to the corresponding alpha-(3,4-dihydroxyphenyl)-beta-(N substituted phenylalkyl)- lIIliI'lOethanol.

This process may be represented as follows:

wherein Y and R have the significance previously assigned.

Some of the nuclear substituted phenylalkyl amines which may be used inthis process are p-methoxyphenyh isopropylamine,o-chlorophenylisopropylamine, m,p-methylenedioxyphenylisopropylamine,p-hydroxyphenylisopropylamine, m,p-methylenedioxyphenylpropylamine,l-p-hydroXyphenyl-3-amino butane and 1-p-methoXyphenyl-4- amino pentane.

The reaction between chloroacetylcatechol and the nuclear substitutedphenylalkyl amine is readily effected in aqueous alcohol at an elevatedtemperature such as the reflux temperature. From 1 to 6 hours isadequate to essentially complete the reaction. The product may berecovered from the reaction mixture by conventional processes such asevaporating the mixture to dryness and recrystallizing the product,generally as an acid addition salt and preferably the hydrochloride,from a lower alcohol such as isopropanol.

Some of the specific intermediate ketones produced in this way are thecompounds of the formula in which R is a p-methOX o-chloro, p-hydroxy orm,pmethylenedioxy group on the phenyl group. Other specific compoundsproduced in this way are 3,4-dihydroxyphenylN-[3-(l-p-methoxyphenylbutyl) ]-aminomethy1 ketone, 3,4-dihydroxyphenylN-(4-p-hydroxyphenylbutyl)- aminomethyl ketone and 3,4-dihydroxyphenylN-[4-(1- rn,p-methylenedioxyphenylpentyl)]-aminomethyl ketone.

3 ed. For the reduction the ketone is advisably employed in the form ofan acid addition salt such as the hydrochloride, sulfate, maleate orcitrate. The reaction product may be recovered from the reaction mixtureby conventional methods. The product of reduction will, of course, bethe alcohol in the form of the corresponding acid addition salt.Conversionfrom a salt to the free base is readily achieved byadding abase, such as sodium hydroxide, to an aqueous solution of the salt.

Some of the specific derivatives produced in this way are the compoundsof the formula in which R is a p-methoxy, o-chloro, p-hydroxy orm,pmethylenedioxy-group on the phenyl .group. Other spedihydroxyphenyl)beta 4 [N 4 (1 p hydroxyphenylpentyl)]-amino ethanol.

The production of alpha-(3,4-dihydroxyphenyl)-beta- N-3,4-methylenedioxyphenyl -isopropylamino ethanol by catalytic reductionof the intermediate ketone yields a mixture of diastereoisomers of thisalcohol. These diastereoisomers may be separated readily byincorporating the diastereoisorneric mixture ofalpha-(3,4-dihydroxyphenyl) beta (N 3',4' methylenedioxyphenyl)isopropylamino ethanol as the hydrochloride salt in hot isopropylalcohol. The fraction insoluble'in hot isoprpyl alcohol isthediastereoisomer melting at 170-172 C. as

the hydrochloride while the soluble diastereoisomer melts at 125127 C.dec. as the hydrochloride.

These fractions were proven to be two disatereoisomers ofalpha-(3,4-dihydroxyphenyl)-beta-(N-3',4-rnethylenedioxyphenyl)isopropylamino ethanolhydrochloride since:

1) Assays for carbon, hydrogen, nitrogen and chlorine Were identical forboth fractions within experimental limits. (2) The two fractionscouldnot be matographic adsorption.

(3) Identical ultraviolet and near infrared spectra were obtained. v

(4) 'The two fractions gave different infrared spectra asdiastereoisorners often do.

separated by chro- '(5) Different X-ray diffractionpatterns wereobtained for, the two fractions indicating difierent crystallinestructures.

. (6) One fraction could not be converted to the otherby 0 crystalseeding. This rules out the possibility of poly morphism.

In normal clinical use the compounds will beemployed in salt form and itis to be understood that the claims hereof cover the salts as'well asthe free'bases. The activity'of the compounds is independent of whetherthey are in salt fornror otherwise. Salts may be prepared by While thesalt norma1- I any of the well known methods. lype'mployed is thehydrochloride, I have prepared other salts-such as the acetate, sulfateand tartrate. u 7 7 Alpha (3,4 gdihydroxyphenyl) 4 beta (3',4J- meth-'ylenedioxy henyl)-is opropylamino,ethanol is considered to be the bestbronchodilator of these novel compounds. It is safe and etfective bothin animals and humans. The high melting diastereoisome'rof this compoundis advisably used, and preferably as the, hydrochloride salt althoughother 'nontoxic saltsmay be employed if desired.

The following are representative pharmaceutical formulationswhich' maybeused to administerthe active agents of thisinvention' and particularlyalpha-( 3,4-dihydroxy- 7 l phenyl) beta (N-3',4' rnethylenedioxyphenyl)isopropylamino ethanol hydrochloride which is referred to in theformulations as LIB-251.

A. Each tablet contains:

B. Each tablet contains:

Pentobarbital,'N.N.R. specifications mg 32.00

JR 251 mg 2.00 Powdered sugar, U.S.P. mg 181.44 I Glucose, U.S.P.-(added as glucose solution, for 7 granulation) Q.s. 'Starch, U.S.P. Q.s.Talc, U.S.P. Q.s. Magnesium stearate, U.S.P. mg 1.52

C. Each tablet contains:

' 13 251;. mg 2.50 Powdered sugar, U.S.P. mg 204.12 Starch, U.S.P. Q.s.

Glucose, U.S.P. (added as glucosesolution, for

granulation) he Q.s. Talc, U.S.P. Q.s. Magnesium stearate, U.S.P. mg1.52 D. Each tablet'con'tains:

Pentobarbital, N.N.R. specifications mg 32.00 JB 251 mg 2.50 Powderedsugar, U.S.P. rn g 181.44 Starch, U.S.P. Q.s. Glucose, U.S.P. (added asglucose solution, for

granulation) Q.s. Talc, U.S.P. V Q.s. Magnesium stearate, U.S.P. mg 1.52The tablets are prepared by combining the 113-251,

sugar, starch and glucose, mixing well, drying the mix- E. Forinhalation, each cc. contains:

I13 251 mg 5.0 Chlorobutanol, hydrous, U.S.P. r'ng 5.0

' 7 Sodium bisulfite, U.S.P; ;mg 1.0 Propyleneglycol, U.S.P. cc 0.8Distilled Water, U.S.P. XIV Q.s.

F. For inhalation, each cc. contains: I 1

JB 251 mg 10.0 Chlorobutanol, hydrous, U.S.P.' mg 5.0

Sodium bisulfite, U.S.P. mg 1.0 Propylene glycol, U.S.P. cc 0.8Distilled water, U.S.P.XIV Q.s.-

-G. For injection,each cc. contains: T

LIB 251 mgc 0.5 Chlorobutanol, hydrous, U.S.P. mg 5.0 Sodiummetabisulfite,'A.R. ;mg 1.0. Water'for injection, U.S.P. Q.s.-

The inhalation and injectiomliquids are prepared by j adding thematerials to the liquid under sterilecondi:

tions.

The following examples illustrate the preparation'of specificcompoundswithin'the scope of this invention.

' EXAMPLE 1 V 3,4-Diltydf0xyphenyl N-(o-Chlorophenylisopropyl)fAminomethyl Ke tone Hydrochloride Aisolution containing 15 g. (0.081mole) of chloro- Stirring and heating were continued for another twohours. The reactionmixture was cooled'andacidified with 15 cc. of conc.HCl and then concentrated in vacuo to a viscous consistency. The residuewas dissolved in hot acetone and seeded with crystals obtained frommethyl ethyl ketone crystallization. On cooling, 13 g. of solid appearedwhich was removed by filtration. The filtrate was concentrated and theresidue crystallized fiom methyl ethyl ketone, yield 19 g., M.P. 170-180C. The solid was suspended in 125 cc. of hot isopropyl alcohol and themixture allowed to cool to room temperature; 9 g. were recovered onfiltration, M.P. 201-203 C.

Analysis.-Calcd. for C17H19C12NO3: Cl, 19.92; N, 3.93. Found: Cl, 20.00;N, 4.02.

EXAMPLE 2 a- (3 ,4 -Dihydroxyphenyl -fi- (N -o-Chloroph enylz'sopropyl)-Amin Ethanol Hydrochloride Three grams of the ketone of Example 1 weredissolved in absolute ethanol and reduced with 0.1 g. of platinum oxideat 60 p.s.i. of hydrogen. The catalyst was removed by filtration and thefiltrate concentrated to dryness. The residue was taken up with acetoneand a very hygroscopic solid isolated, M.P. 70 C. dec.

EXAMPLE 3 3,4-Dihydroxyphenyl-N-(3',4'-Methylenedioxyphenyl)-Isopropylaminomethyl Ketone Hydrochloride To 56 g. (0.31 M) of3,4-methylenedioxyphenylisopropylamine in 80 cc. of 60% aqueous ethanolwere added 20 g. (0.11 M) of chloroacetyl catechol in 100 cc. ofabsolute ethanol. The mixture was stirred and heated at 70 C. for 6hours, cooled and acidified with 20 cc. of conc. HCI. On cooling, 17 g.(43%) of prodnot separated, M.P. 225227 C. dec. After suspension in hotisopropyl alcohol 16.5 g. of the solid were recovered, M.P. 232234 C.dec.

Analysis.-Calcd. for C H ClNO Cl, 9.70; N, 3.84. Found: Cl, 9.59; N,3.84.

EXAMPLE 4a-(3,4-Dihydroxyphenyl)-5-(N-3',4'-Methylenedioxyphenyl)-Is0propylaminoEthanol Hydrochloride Fifteen grams (0.043 M) of the ketone of Example 3dissolved in 300 cc. of 50% aqueous ethanol were subjected tohydrogenation with 2 g. of palladium-oncharcoal catalyst at 60 p.s.i. ofhydrogen. The catalyst was removed by filtration and the filtrateconcentrated to dryness. The residue was crystallized from hot acetone,M.P. 126127 C. dec., yield 9.0 g. (65%).

Analysis.Calcd. for C H ClNO Cl, 9.68; N, 3.81. Found: Cl, 9.60; N,3.76.

The base was prepared by neutralization of an aqueous solution of thehydrochloride salt with an equivalent amount of 1.06 N sodium hydroxidesolution; M.P. 163 C.

Analysis.Calcd. for C H NO N, 4.24. Found: N, 4.12.

EXAMPLE 5 To 50 g. (0.30 M) of p-methoxyphenylisopropylamine in 80 cc.of 60% aqueous ethanol were added 18.5 g. (0.10 M) of chloroacetylcatechol in 100 cc. of ethanol durin a period of one hour at 6065 C.Heating and stirring were continued for 5 hours, the reaction mixtureacidified with cc. of cone. HCl and concentrated to a viscousconsistency. 'l' he residue was suspended twice in 600 cc. of hotisopropyl alcohol and the mixture filtered hot, yield 14 g. (39%), M.P.203-205 C. dec.

Analysis.Calcd. for C H ClNO C1, 10.11 N, 3.99. Found: Cl, 9.89; N,3.97.

6 EXAMPLE 6 a-(3,4-Dihydroxyphenyl)-,8-(N-4-Methoxyphenylisopropyl)-Aminoethanol Hydrochloride An alcoholicsolution containing 7.0 g. (0.02 M) of the ketone of Example 5 wassubjected to hydrogenation with 0.2 g. PtO as in Example 2; the productwas isolated as shown in Example 4, yield 3.6 g. (60%), M.P. l22123 C.dec.

Analysis.Calcd. for C H ClNQ Cl, 10.05; N, 3.97. Found: Cl, 9.86; N,3.97.

EXAMPLE 7 3,4-Dihydroxyphenyl N- (Z-ZJethoxyphenylisopropyl) A minornezhyl Ketone Hydrochloride This compound was prepared by theprocedure de scribed in Example 5 using o-methoxyphenylisopropylamine;yield 35%, M.P. 183185 C.

Alialysis.Calcd. for c H ClNO z Cl, 10.11; N, 3.99. Found: Cl, 10.26; N,4.00

EXAMPLE 8 w(3,4-Dihydroxyphenyl) -,B-N-(Z-Methoxyphenylisopropyl)-Aminoethanol Hydrochloride This compound wasprepared by the reduction of the ketone of Example 7, according to theprocedure outlined in Example 4; yield 60%, M.P. 130131 C.

Analysis.-Calcd. for C H ClNO Cl, 10.05; N, 3.97. Found: Cl, 9.95; N,3.85.

EXAMPLE 9 3,4-Dz'hydroxyphenyl N-(4-Hydroxyphenylisopropyl)- AminomethylKetone Hydrobromide Fifty grams of the p-methoxy compound of Example 5was treated with 500 cc. of 48% aqueous hydrobromic acid and the mixturerefluxed with stirring for 2 hours and the crude product isolated byfiltration on cooling. After recrystallization from 230 cc. of water,the product melted at l55-157 C. dec., yield 43.6 g.

Analysis.-Calcd. for C H BrNO Br, 20.95; C, "53.56; H, 5.27; N, 3.67.Found: Br, 21.01; C, 53.41; H, 5.72; N, 3.56.

The hydrochloride salt was prepared by dissolving 41.6 g. of thehydrobromide salt in 218 cc. of hot Water and treating the solution with252 cc. of cone. hydrochloric acid solution, yield 29 g., M.P. 163165 C.

Analysis.-Calcd. for C H ClNO Cl, 10.51; N, 4.15. Found: Cl, 10.88; N,3.97.

A methanolic solution containing 28.5 g. (0.075 mole) of the ketone .HClof Example 9 was reduced with 4.5

g. of 10% palladium-on-carbon catalyst and theproduct I crystallizedfrom acetone, M.P. 8991 C. dec.

Analysis.Calcd. for C H C1NO Cl, 10.45; N, 4.12. Found: Cl, 10.42; N,3.90.

The hydrobromide salt obtained from the ketone .HBr of Example 9 meltedat C. dec.

Analysis.Calcd. for C17H22BI'NO4: Br, 20.85; N, 3.65. Found: Br, 20.71;N, 3.72.

EXAMPLE 11 High Melting oc- (3,4-Dihydroxy phenyl -,8- (N -3 ',4'- Methylenedioxy phenyl Jsopropylamino Ethanol A mixture containing 25.7 g.0.07 mole) of 3,4-dihy- ,by filtration.

' the formulae by vacuum distillationand the residue dissolved in hotacetone (300 cc.). .On standing, a crystalline precipitate appearedwhich was collected by filtration, yield 23 g.

'(89%), MP. ISO-151 C.

The above precipitate was suspended in 75 cc. of hot isopropyl alcoholand'the mixture allowed to reflux for a one hour. .The insolublematerial was separated by filtering the hot suspension and 15.6 g. (68%)of the high melting diastereoisomer oc- (3 ,4-dihydroxyphenyl) -fi- (N-3',4-methylenedioxyphenyl)-isopropylamino ethanol hydrochloride wasobtained, MP. 170171 C.

An aqueous solution of the hydrochloride salt (3.67 g. in .100 cc. ofWater) was clarified by filtration and then neutralized with 9.5 cc. of1.06 N aqueous sodium hydIOXidG. A White product precipitated and wasisolated The precipitate of alpha-(3,4-dihydroxy henyD-beta-(N 3',4'methylenedioxyphenyl)-isopropylamino ethanol was washed with acetone,yield 3.2 g. (97%),'M.P. 163 c. dec. 7 V

Analysis. Calcd. for C H NO N, 4.24. Found? Various changes andmodifications of the invention can be made and, to'the extent that suchVariations incorporate the spirit of this invention, they are intendedto be included within the scope of the appended claims.

What is claimed is: p 1. A member of the group consisting of compoundsof wherein R is a member of the group consisting of lower alkoxy, haloand .hydroxy, and nontoxic acid addition salts thereof. Y

2.- Compounds of the formula 7 wherein R is lower alkyl. 7'

3. Compound of the tormula 4. Compoundof the formula CH HO 5. Compoundof the formula or OH References Cited in the file of this patent UNITEDSTATES PATENTS Stolz etal, June 13, 1933 OTHER REFERENCES Surrey:Journal of the American Chemical Society, vol.

70, page 2887 (1948).

Moed et al.: Rec. des Trav. Chim. des Pays-Bats, vol.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE